The goal of this application is to support the development of Dr. Allan Berger as a clinician scientist so that at the completion of the award he will be an independent researcher and an outstanding academic scientist and clinician. Dr. Michael J. Welsh will assume responsibility as mentor to ensure the success of the development plan. The heart of the proposal is an intensive training experience in the basic research laboratory. Cystic fibrosis (CF) is the most common lethal genetic disease in young Caucasians, and is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. ATP binding to the two nucleotide binding domains (NBD) of CFTR is required for normal channel function. In this proposal, Dr. Berger will explore the interactions between ATP and CFTR. Preliminary data suggest that certain novel missense mutations in CFTR selectively block ATP binding. There are three Specific Aims. 1) What are the biochemical and functional effects of mutations that block ATP binding to CFTR? 2) What are the effects of the Walker A lysine mutations K464A and K1250A on ATP binding? 3) What residues in CFTR contact the ATP base? Together these aims will determine the functional mechanisms underlying ATP regulation of the CFTR chloride channel and structural mechanisms of ATP binding. Dr. Berger will combine biochemical and functional assays to learn how ATP interacts with the NBDs to control channel activity. Dr. Berger will further develop his skills at using the scientific method to develop hypotheses that can be experimentally tested to yield unequivocal answers. In addition to basic research training, Dr. Berger will improve his skills of presenting data verbally and in writing. He will continue his training by participating in seminars and journal clubs, and will attend national meetings to present his own work and to learn from others. He will receive instruction in the responsible conduct of research. He will also receive instruction and critique in grant writing. In the latter stages of this training he will prepare grant applications for independent research funding. Both the mentor and the institution are highly committed to the applicant's scientific development and academic success.